1. Field of Invention
The invention relates to crystalline polymorphs of a polycyclic xanthine phosphodiesterase (“PDE”) V inhibitor.
2. Background
WO 02/24698, which is incorporated herein by reference in its entirety, teaches a class of xanthine PDE V inhibitor compounds useful for the treatment of impotence. A general process disclosed therein (page 75, line 6 to page 80, line 2) for preparing xanthine PDE V inhibitor compounds having the formula (I) follows:
    (i) reacting a compound having the formula (III) with an alkyl halide in the presence of a base (introduction of R2 or a protected form of R2);    (ii) (a) debenzylating and then (b) alkylating the compound resulting from step (i) with an alkyl halide, XCH2R3;    (iii) (a) deprotonating and then (b) halogenating the compound resulting from step (ii);    (iv) reacting the compound resulting from step (iii) with an amine having the formula R4NH2; and    (v) removing a protecting portion of R2, if present, on the compound resulting from step (iv) to form the compound having the formula (I).R1, R2, R3 and R4 are each defined in WO 02/24698.
WO 02/24698 (pages 44 & 68–73) further teaches a synthesis for a specific xanthine PDE V inhibitor compound identified therein as Compound 13 or Compound 114 of Table II. Compound 13 can be named as 1-ethyl-3,7-dihydro-8-[(1R,2R) -(hydroxycyclopentyl)amino]-3-(2-hydroxyethyl)-7-[(3-bromo-4-methoxyphenyl)methyl]-1H-Purine-2,6-dione:
Compound 13 exhibits good PDE V inhibitor activity (potency) and selectivity, and is useful for treating erectile dysfunction. However, when made according to the process described in WO 02/24698, Compound 13 can exhibit some undesirable properties with respect to thermodynamic stability.
Polymorphism can be characterized as the ability of a compound to crystallize into different crystal forms, while maintaining the same chemical formula. Polymorphs of a given drug substance are chemically identical in containing the same atoms bonded to one another in the same way, but differ in their crystal forms, which can affect one or more physical properties, such as solubility, melting point, bulk density, flow properties, etc.
It would be beneficial to improve the thermodynamic properties of Compound 13. It would further be beneficial to produce Compound 13 in a stable crystalline form, which has consistent physical properties. The invention seeks to provide these and other benefits, which will become apparent as the description progresses.